Abstract Hepatitis C virus (HCV) often causes persistent infection, and is an increasingly important factor in the etiology of hepatocellular carcinoma (HCC). There is no preventive or therapeutic hepatitis C vaccine available. Direct antiviral agents have significantly improved outcome of HCV infection, although it does not prevent reinfection. Further, the treatment is costly and already faces new issues, such as viral mutation. Recent studies suggested that some patients still progress to liver failure and/or cancer despite being cured of infection after therapy. Therefore, studies are extremely urgent to understand the underlying mechanisms of HCV associated liver pathogenesis. We and others have shown transcriptional regulatory activities of hepatitis C proteins on a number of cellular genes, which may form the genetic basis for malignant transformation of infected hepatocytes. Since hepatitis C causes silent disease initially, we do not know when infected cells transform and who the players are along with viral proteins. Thus, our overall goal in this grant application is to delineate the mechanisms of hepatitis C mediated HCC. We observed that hepatitis C modulates microRNAs (miRNA) that can influence hepatocyte growth. We recently observed that hepatitis C infection of primary human hepatocytes induces phenotypic changes by enhancing epithelial mesenchymal transition (EMT) related gene expression, and generates tumor initiating stem-like cells (TISCs). Based on the novel information, we hypothesize that hepatitis C modulates miRNAs and signaling pathways concurrently to promote hepatocyte growth, leading to HCC progression. We will validate our key observations using liver biopsy specimens from hepatitis C infected patients to maintain human relevance. Examining essential steps for inhibition will open up new avenues for developing effective treatment strategies against this highly prevalent disease.